Early Radiation Boosts Prostate Cancer Survival

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

In this randomized study, adjuvant radiotherapy after radical prostatectomy compared with wait-and-see was safe in pT3 prostate cancer. At 10 years' median follow-up, adjuvant radiotherapy was associated with significantly better biochemical control, but the study was not powered to detect differences in overall survival.

ORLANDO -- Immediate radiation therapy after radical prostatectomy led to a 50% increase in long-term biochemical progression-free survival (bNED) for patients with locally advanced prostate cancer, according to a study reported here.

After a median follow-up of almost 10 years, patients who received immediate adjuvant radiotherapy had a bNED rate of 61% compared with 40% for patients randomized to a "wait-and-see" strategy that depended on a return of detectable PSA levels, Thomas Wiegel, MD, said at the Genitourinary Cancers Symposium.

Patients with positive surgical margins benefited the most from immediate radiotherapy, reflected in a bNED rate of 55% versus 27% for patients randomized to the wait-and-see (salvage) approach.

Overall survival and distant metastasis-free survival did not differ between groups, primarily because of low rates of qualifying events in both groups, said Wiegel, of the University of Ulm in Germany.

"The greatest impact was observed in patients who had positive surgical margins and those with pT3a/b disease," said Wiegel. "Adjuvant radiation therapy had no influence on overall survival, but the trial was not statistically powered for a survival analysis.

"There was a low rate of late side effects, and a low rate of overtreatment of patients with locally advanced disease and positive surgical margins."

The findings corroborated but also clarified the benefits of adjuvant radiation therapy for locally advanced prostate cancer (pT3 R1/0).

A European cooperative-group trial showed a 20% improvement in bNED 10 years after diagnosis, but no effect on overall or metastasis-free survival (Lancet 2012; 380: 2018-2027). In contrast, investigators in the U.S. found that immediate radiation therapy improved all three outcomes after 12 years of follow-up (J Urol 2009; 181: 956-962).

Wiegel and colleagues previously reported improved 5-year bNED with immediate radiation therapy but no difference in overall or metastasis-free survival (J Clin Oncol 2009; 27: 2924-2930). The results remained unchanged after another 5 years of follow-up.

The trial initially involved 395 men with locally advanced disease, all of whom underwent radical prostatectomy. Within 2 weeks of surgery (before PSA had fallen to undetectable levels), the men were randomized to radiation therapy or the wait-and-see strategy.

Subsequently, 78 patients did not achieve undetectable PSA levels (<0.05 ng/mL) after surgery, and they were excluded from the trial. Additionally, 34 patients allocated to radiation therapy did not receive treatment, and they also were excluded, leaving 273 patients for follow-up.

Eligible patients had prostate cancer with extracapsular extension or seminal vesicle involvement but no nodal involvement or metastases. Patients randomized to immediate treatment received 3D conformal radiation at a total dose of 60 Gy.

Investigators defined progression as the first detectable PSA measurement that was confirmed by a follow-up test. The primary endpoint was bNED.

The 5-year data showed bNED rates of 72% with immediate radiation therapy and 54% with the wait-and-see strategy. Though rates declined in both arms between 5 and 10 years, the magnitude of the difference favoring immediate treatment increased. The hazard ratio for progression was 0.53 after 5 years and 0.51 after 10 years (P=0.000022).

Metastasis-free survival did not differ between groups, but Wiegel noted that qualifying events had occurred in only 17% of patients. Similarly, overall survival did not differ, as the rate of qualifying events was 15% in the two treatment arms combined.

Multivariate analysis identified three significant predictors of increased risk of progression, whereas radiation therapy was the only significant predictor of a decreased risk of progression:

Gleason score >6 -- RR 1.44, P=0.038

≥pT3c -- RR 1.80, P=0.00037

Positive surgical margins -- RR 1.59, P=0.0092

Immediate radiotherapy -- RR 0.46, P=0.000005

The 5-year data showed low rates of acute radiation toxicity, and the favorable profile persisted with late toxicity, including grade III bladder toxicity in 1% of patients, stricture in 3% (versus 1% of the wait-and-see group), and no grade III rectal toxicity (1% grade II).

Wiegel also addressed the criticism that adjuvant radiation therapy is overtreatment. The persistent and increasing disparity in progression-free survival between treatment groups provided a strong argument against overtreatment.

"We also know that 30% to 40% of patients will not profit from salvage radiotherapy," said Wiegel. "It is incorrect to say that, for our best patients, adjuvant radiotherapy is overtreatment."

Invited discussant Anthony D'Amico, MD, of Harvard, sought to explain the discordant results between the findings of the U.S. study (improved overall and metastasis-free survival) versus the European and German trials. He suggested the timing of salvage radiation therapy could account for the difference.

More patients in the observation arms of the European and German trials received early salvage radiation therapy compared with those in the U.S. trial. For example, 33% of the observation group in the European trial received early salvage therapy, whereas 20% did so in the U.S. trial.

"Delayed salvage radiation therapy occurring in 13% more patients in the [U.S.] trial as compared to the [European/German] participants on the watchful waiting arm could explain the discordant results," said D'Amico.

"Early salvage radiation therapy, when the PSA level is greater than 0.1, may produce the same result as adjuvant (immediate) radiation therapy," he added. "We are awaiting results of randomized trials to determine that. Until then, we can consider adjuvant radiation therapy based on the number of risk factors in order to reduce overtreatment."

The Genitourinary Cancers Symposium is cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology.

The study was supported by German Cancer Aid.

Wiegel and co-investigators had no relevant disclosures.

D'Amico had no relevant disclosures.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

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